Leukotriene receptor antagonists in children with cystic fibrosis lung disease : anti-inflammatory and clinical effects.
TL;DR: Evidence that amelubant metabolism in adult and pediatric patients with CF is similar to that in healthy adults is provided, and the dose of montelukast and the administration interval does not need to be modified if the goal is to mimic the serum concentrations used to treat asthma is provided.
Abstract: Cystic fibrosis (CF) lung disease is characterized by chronic endobronchial infection resulting in progressive pulmonary destruction; this is a major cause of mortality and morbidity. Neutrophils are the primary effector cells responsible for the progressive deterioration of lung function. Peptido-leukotriene B4 antagonists, new anti-inflammatory agents that block the neutrophil-dominated inflammation, could have had the potential for long-term use. A trial on the pharmacokinetics of amelubant administered orally as a single dose of up to 75 mg in pediatric patients with CF and 300 mg in adults, and as a repeated dose of 75 mg and 150 mg, respectively, once daily for 15 days provided evidence that amelubant metabolism in adult and pediatric patients with CF is similar to that in healthy adults. In another study using the same dosage regimen, amelubant appeared to be safe and well tolerated. Safety measures included physical examination, vital signs, spirometry, oximetry, ECG, and clinical laboratory testing. However, a randomized, double-blind, placebo-controlled, multinational, phase II trial (Boehringer Ingelheim 543.45) was conducted to investigate the clinical efficacy of 24 weeks of treatment with amelubant in patients with CF with mild-to-moderate lung disease. Two doses of amelubant (75 and 150 mg) were tested in adult patients (> or = 18 years) and one dose of amelubant (75mg) was tested in pediatric (6-17 years) patients. The trial was terminated early due to a statistically significant increase in the risk of pulmonary-related, serious adverse events in adults receiving amelubant. Cysteinyl leukotrienes, eosinophilic inflammation, and viral infections also contribute to progressive pulmonary destruction in CF. Cysteinyl leukotrienes are potential targets for cysteinyl leukotriene receptor antagonist use. A study on the pharmacokinetics of montelukast in children with CF provided evidence that the dose of montelukast and the administration interval does not need to be modified if the goal is to mimic the serum concentrations used to treat asthma. In a randomized, double-blind, crossover, placebo-controlled study, 16 children with mild CF (median age 9.5 years; vital capacity [VC] >70%) were treated with montelukast (5 to 14 years; 10 mg) or placebo as a once-daily tablet for 21 days. There was a significant (p < or = 0.02) reduction in serum eosinophil cationic protein levels and eosinophils (p < or = 0.027) with montelukast. However, neither lung function tests (VC, forced expiratory volume in 1 second [FEV1], maximum expiratory flow at 25% of forced VC), nor clinical symptom scores changed significantly. In another study, 26 patients aged 6-18 years with moderate CF (VC between 40% and 69% predicted) received montelukast or placebo for 8 weeks in a 20-week, randomized, double-blind, crossover, placebo-controlled trial. After treatment with montelukast there was a significant improvement in FEV1, peak expiratory flow, and forced expiratory flow between 25% and 75%, and a significant decrease in cough and wheezing scale scores (p < 0.001 for all). Montelukast treatment decreased serum and sputum levels of eosinophil cationic protein and interleukin-8 (IL-8), decreased sputum levels of myeloperoxidase, and increased serum and sputum levels of IL-10 (p < 0.001 for all) compared with placebo. To date, clinical experience and research data on the anti-inflammatory effects of leukotriene receptor antagonists in CF are limited. Multicenter trials with longer observation periods and greater patient numbers are needed to prove the hypothesis that leukotriene receptor antagonists have the potential to ameliorate CF lung disease with long term use.
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TL;DR: High-dose oral N-acetylcysteine has the potential to counter the intertwined redox and inflammatory imbalances in CF.
Abstract: Neutrophilic airway inflammation is a hallmark of cystic fibrosis (CF). As high oxidant producers, airway neutrophils contribute largely to the systemic redox imbalance seen in CF. In turn, this chronic and profound imbalance can impact circulating neutrophils before their migration into airways. Indeed, in 18 CF patients with stable disease, blood neutrophils were readily deficient in the pivotal antioxidant glutathione (P = 0.003, compared with 9 healthy controls). In a phase 1 study, this deficiency was improved (P = 0.025) by the glutathione prodrug N-acetylcysteine, given orally in high doses (0.6 to 1.0 g three times daily, for 4 weeks). This treatment was safe and markedly decreased sputum elastase activity (P = 0.006), the strongest predictor of CF pulmonary function. Consistently, neutrophil burden in CF airways was decreased upon treatment (P = 0.003), as was the number of airway neutrophils actively releasing elastase-rich granules (P = 0.005), as measured by flow cytometry. Pulmonary function measures were not improved, as expected with short-term treatment. After excluding data from subjects without baseline airway inflammation, positive treatment effects were more pronounced and included decreased sputum IL-8 levels (P = 0.032). Thus, high-dose oral N-acetylcysteine has the potential to counter the intertwined redox and inflammatory imbalances in CF.
249 citations
TL;DR: The recent findings on leukotriene receptors are covered to revisit them as new drug targets.
Abstract: Leukotrienes, a class of arachidonic acid-derived bioactive molecules, are known as mediators of allergic and inflammatory reactions and considered to be important drug targets. Although an inhibitor of leukotriene biosynthesis and antagonists of the cysteinyl leukotriene receptor are clinically used for bronchial asthma and allergic rhinitis, these medications were developed before the molecular identification of leukotriene receptors. Numerous studies using cloned leukotriene receptors and genetically engineered mice have unveiled new pathophysiological roles for leukotrienes. This Review covers the recent findings on leukotriene receptors to revisit them as new drug targets.
115 citations
Cites background from "Leukotriene receptor antagonists in..."
...LY293111 was also tested in cystic fibrosis (84) and chondrosarcoma and melanoma (85, 86) without significant effectiveness....
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TL;DR: The outcome of this trial provides a cautionary tale for the administration of potent anti-inflammatory compounds to individuals with chronic infections, as the potential to significantly suppress the inflammatory response may increase the risk of infection-related adverse events.
114 citations
Cites background from "Leukotriene receptor antagonists in..."
...The cysteinyl leukotriene receptor antagonist, montelukast, is frequently used to treat asthma, and has been used in patients with CF (particularly in those with bronchial hyperreactivity) with some evidence for benefit without apparent complications that would limit their use [37]....
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...The former contributes to neutrophilic inflammation in the lung, while the latter, produced predominantly by eosinophils, mast cells, and macrophages, contribute to non-neutrophilic pulmonary inflammation [37]....
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TL;DR: Evidence is presented for the cysteinyl leukotrien–independent mechanisms of action of montelukast and their potential clinical relevance, suggesting that this agent may have a broader spectrum of anti-inflammatory activities than originally thought.
Abstract: The prototype cysteinyl leukotriene receptor antagonist, montelukast, is generally considered to have a niche application in the therapy of exercise- and aspirin-induced asthma. It is also used as add-on therapy in patients whose asthma is poorly controlled with inhaled corticosteroid monotherapy, or with the combination of a long-acting beta(2)-agonist and an inhaled corticosteroid. Recently, however, montelukast has been reported to possess secondary anti-inflammatory properties, apparently unrelated to conventional antagonism of cysteinyl leukotriene receptors. These novel activities enable montelukast to target eosinophils, monocytes, and, in particular, the corticosteroid-insensitive neutrophil, suggesting that this agent may have a broader spectrum of anti-inflammatory activities than originally thought. If so, montelukast is potentially useful in the chemotherapy of intermittent asthma, chronic obstructive pulmonary disease, cystic fibrosis, and viral bronchiolitis, which, to a large extent, involve airway epithelial cell/neutrophil interactions. The primary objective of this mini-review is to present evidence for the cysteinyl leukotriene-independent mechanisms of action of montelukast and their potential clinical relevance.
87 citations
Cites background from "Leukotriene receptor antagonists in..."
...In CF, the inflammatory mediators and mechanisms involved are such that they could be considered potential targets for both LTB4 receptor and CysLT1R antagonism[64], with several studies having documented the benefit of montelukast[65,66]....
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TL;DR: The data show for the first time that LTD(4), via the CysLT1 receptor, can transcriptionally activate IL-8 production, with involvement of the transcription factors p50, p65, Fos, and Jun and upregulates the expression of c-fos and c-jun at the mRNA level.
Abstract: Because cysteinyl-leukotrienes (cysLTs) are major protagonists in the pathophysiology of human asthma, and because neutrophils are involved in the more severe form of asthma, we studied the potential for leukotriene (LT) D4 to induce synthesis of the chemokine IL-8 through activation of the CysLT1 receptor. We found LTD4 to induce IL-8 gene expression in monocytic THP-1 cells and human dendritic cells with complete abrogation by selective CysLT1 antagonists. Human embryonic kidney–293 cells stably transfected with CysLT1 were used to better study the transcriptional regulation of the IL-8 promoter. Stimulation of the cells with graded concentrations of LTD4 resulted in a time- and concentration-dependent induction of IL-8 transcription and protein synthesis. Use of IL-8 promoter mutants with substitutions in their NF-κB, activator protein (AP)–1, and NF–IL-6 binding elements revealed a requirement for NF-κB and AP–1, but not NF–IL-6, in LTD4-induced activation of the IL-8 promoter. Overexpression of domin...
59 citations
References
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TL;DR: Leukotrienes C4, D4, and E4, which are released from the lung tissue of asthmatic subjects exposed to specific allergens, seem to play a pathophysiological role in immediate hypersensitivity reactions.
Abstract: Arachidonic acid plays a central role in a biological control system where such oxygenated derivatives as prostaglandins, thromboxanes, and leukotrienes are mediators. The leukotrienes are formed by transformation of arachidonic acid into an unstable epoxide intermediate, leukotriene A4, which can be converted enzymatically by hydration to leukotriene B4, and by addition of glutathione to leukotriene C4. This last compound is metabolized to leukotrienes D4 and E4 by successive elimination of a gamma-glutamyl residue and glycine. Slow-reacting substance of anaphylaxis consists of leukotrienes C4, D4, and E4. The cysteinyl-containing leukotrienes are potent bronchoconstrictors, increase vascular permeability in postcapillary venules, and stimulate mucus secretion. Leukotriene B4 causes adhesion and chemotactic movement of leukocytes and stimulates aggregation, enzyme release, and generation of superoxide in neutrophils. Leukotrienes C4, D4, and E4, which are released from the lung tissue of asthmatic subjects exposed to specific allergens, seem to play a pathophysiological role in immediate hypersensitivity reactions. These leukotrienes, as well as leukotriene B4, have pro-inflammatory effects.
2,676 citations
TL;DR: The cloning of the complementary DNA encoding a cell-surface LTB4 receptor that is highly expressed in human leukocytes is reported, showing that L TB4 is a unique lipid mediator that interacts with both cell- surface and nuclear receptors.
Abstract: Leukotriene B4(LTB4)1 is a potent chemoattractant that is primarily involved in inflammation, immune responses and host defence against infection2. LTB4 activates inflammatory cells by binding to its cell-surface receptor (BLTR)3. LTB4 can also bind and activate the intranuclear transcription factor PPARα, resulting in the activation of genes that terminate inflammatory processes4. Here we report the cloning of the complementary DNA encoding a cell-surface LTB4 receptor that is highly expressed in human leukocytes. Using a subtraction strategy, we isolated two cDNA clones (HL-1 and HL-5) from retinoic acid-differentiated HL-60 cells. These two clones contain identical open reading frames encoding a protein of 352 amino acids and predicted to contain seven membrane-spanning domains, but different 5′-untranslated regions. Membrane fractions of Cos-7 cells transfected with an expression construct containing the open reading frame of HL-5 showed specific LTB4 binding, with a Kd(0.154nM) comparable to that observed in retinoic acid-differentiated HL-60 cells. In CHO cells stably expressing this receptor, LTB4 induced increases in intracellular calcium, D-myo-inositol-1,4,5-triphosphate (InsP3) accumulation, and inhibition of adenylyl cyclase. Furthermore, CHO cells expressing exogenous BLTR showed marked chemotactic responses towards low concentrations of LTB4 in a pertussis-toxin-sensitive manner. Our findings, together with previous reports4,5, show that LTB4 is a unique lipid mediator that interacts with both cell-surface and nuclear receptors.
1,012 citations
"Leukotriene receptor antagonists in..." refers background in this paper
...[10] Immediately after LTB4 binds to its CF....
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TL;DR: Originally considered as only a paediatric pathogen, respiratory syncytial virus (RSV) has recently been shown to be a significant cause of respiratory illness among elderly and high-risk adults and vaccine against RSV remain an unachieved goal.
Abstract: Respiratory syncytial virus (RSV) is now recognized as a significant problem in certain adult populations. These include the elderly, persons with cardiopulmonary diseases, and immunocompromised hosts. Epidemiological evidence indicates that the impact of RSV in older adults may be similar to that of nonpandemic influenza. In addition, RSV has been found to cause 2 to 5% of adult community-acquired pneumonias. Attack rates in nursing homes are approximately 5 to 10% per year, with significant rates of pneumonia (10 to 20%) and death (2 to 5%). Clinical features may be difficult to distinguish from those of influenza but include nasal congestion, cough, wheezing, and low-grade fever. Bone marrow transplant patients prior to marrow engraftment are at highest risk for pneumonia and death. Diagnosis of RSV infection in adults is difficult because viral culture and antigen detection are insensitive, presumably due to low viral titers in nasal secretions, but early bronchoscopy is valuable in immunosuppressed patients. Treatment of RSV in the elderly is largely supportive, whereas early therapy with ribavirin and intravenous gamma globulin is associated with improved survival in immunocompromised persons. An effective RSV vaccine has not yet been developed, and thus prevention of RSV infection is limited to standard infection control practices such as hand washing and the use of gowns and gloves.
591 citations
TL;DR: Montelukast was generally well tolerated, with an adverse event profile comparable with that of placebo as mentioned in this paper, and significantly improved asthma control during a 12-week treatment period, compared with placebo.
Abstract: Objectives To determine the clinical effect of oral montelukast sodium, a leukotriene receptor antagonist, in asthmatic patients aged 15 years or more. Design Randomized, multicenter, double-blind, placebo-controlled, parallel-group study. A 2-week, single-blind, placebo run-in period was followed by a 12-week, double-blind treatment period (montelukast sodium, 10 mg, or matching placebo, once daily at bedtime) and a 3-week, double-blind, washout period. Setting/Patients Fifty clinical centers randomly allocated 681 patients with chronic, stable asthma to receive placebo or montelukast after demonstrating a forced expiratory volume in 1 second 50% to 85% of the predicted value, at least a 15% improvement in forced expiratory volume in 1 second (absolute value) after inhaled β-agonist administration, a minimal predefined level of daytime asthma symptoms, and inhaled β-agonist use. Twenty-three percent of the patients used concomitant inhaled corticosteroids. Primary End Points Forced expiratory volume in 1 second and daytime asthma symptoms. Results Montelukast improved airway obstruction (forced expiratory volume in 1 second, morning and evening peak expiratory flow rate) and patient-reported end points (daytime asthma symptoms, "as-needed" β-agonist use, nocturnal awakenings) ( P P P Conclusions Montelukast, compared with placebo, significantly improved asthma control during a 12-week treatment period. Montelukast was generally well tolerated, with an adverse event profile comparable with that of placebo.
486 citations
TL;DR: Montelukast improves morning FEV1 in 6- to 14-year-old children with chronic asthma, and this is the first study of its kind to study children younger than 12 years with asthma using a leukotriene receptor antagonist.
Abstract: Context.—Leukotrienes are important mediators of asthma by causing bronchoconstriction,
mucous secretion, and increased vascular permeability. Studies using compounds
that block leukotrienes have demonstrated improvement in asthma control in
adults and adolescents, but children younger than 12 years, for whom asthma
is the most common chronic disease, have not been studied.Objective.—To determine the clinical effect of montelukast, a leukotriene receptor
antagonist, in 6- to 14-year-old children with asthma.Design.—Eight-week, multicenter, randomized, double-blind study.Setting.—Forty-seven outpatient centers at private practices and academic medical
centers in the United States and Canada.Patients.—A total of 336 children with forced expiratory volume in 1 second (FEV1) between 50% to 85% of the predicted value, at least 15% reversibility
after inhaled β-agonist administration, a minimal predefined level of
daytime asthma symptoms, and daily β-agonist use. Concomitant inhaled
corticosteroids at a constant daily dose were used by 39% of patients receiving
montelukast and 33% receiving placebo.Intervention.—After a 2-week placebo run-in period, patients received either montelukast
(5-mg chewable tablet) or matching-image placebo once daily at bedtime for
8 weeks.Main Outcome Measure.—Morning FEV1 percent change from baseline.Results.—Mean morning FEV1 increased from 1.85 L to 2.01 L in the
montelukast group and from 1.85 L to 1.93 L in the placebo group. This represents
an 8.23% (95% confidence interval [CI], 6.33% to 10.13%) increase from baseline
in the montelukast group and a 3.58% (95% CI, 1.29% to 5.87%) increase from
baseline in the placebo group (P<.001 for montelukast
vs placebo).Conclusion.—Montelukast improves morning FEV1 in 6- to 14-year-old children
with chronic asthma.
473 citations